IUD Arrangement

ABSTRACT

An intrauterine device of the type having an external surface contacting the walls of the uterus after insertion therein, and said device having first walls defining a fluid-receiving cavity in at least a portion thereof. A concentrated fluid solution of a drug is present in the cavity and the drug is of the type providing an antifibrinolytic, an antifertility and antiproteolytic effect and is one or a mixture of more than one guanidine such as any aromatic monoguanidine, aromatic diguanidine, non-aromatic monoguanidine and non-aromatic diguanidine, and mixtures of one or more of the guanidines with one or more amidines.

REFERENCE TO RELATED APPLICATIONS

This application is related to and is a continuation-in-part of myco-pending United States patent applications, Ser. Nos. 927,765 filedJuly 25, 1978, 928,093 filed July 26, 1978 (now U.S. Pat. No.4,233,698), 928,106 filed July 26, 1978, and is related to my co-filedand co-pending United States patent applications Ser. Nos. 55,900 and55,903, both filed July 9, 1979, and the teaching and technology of eachof the above identified patent applications is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to an improved intrauterine device wherein thereis a cavity provided in at least a portion of the intrauterine deviceand a concentrated fluid solution of a drug providing antifibrinolytic,antifertility and antiproteolytic effect is provided within the cavity.The cavity walls are defined by a polymer having a predeterminedpermeability of the drug.

2. Description of the Prior Art

Many forms and configurations of intrauterine devices designed toprevent conception in the female have heretofore been utilized. Suchdevices have been provided in a variety of shapes, such as the "T"device shown in U.S. Pat. No. 3,533,406, the Loop, such as shown in U.S.Pat. No. 3,200,815, a "Y" configuration, generally termed a "Ypsilon"configuration, a ring or modified ring such as the Ota ring, and manymodifications thereto, including flat, leaf-like members between varioussegments of the intrauterine device. Such intrauterine devices whichwere not provided with any medications associated therewith dependedupon their presence in the uterus to prevent conception.

Further, other intrauterine devices (IUDs) have incorporated acontrolled release rate medication or drug therein to further aid theanticonceptive action thereof. Such medicated IUDs have generallyemployed copper or progesterone as the contraceptive or antifertilityagent. However, it has been found that copper-releasing intrauterinedevices, as well as non-medicated intrauterine devices still resulted inpain and cramping to the wearer, as well as metrorrhagia andmenorrhagia. Consequently, the excessive uterine hemorrage, with orwithout pain, continues to be a leading cause for this type ofintrauterine device removal. The progesterone-releasing intrauterinedevices are associated with significantly less bleeding than otherdevices but they appear to be associated with a serious complicationapparently produced by the release of progesterone. This complication isectopic pregnancy.

Nevertheless, the general convenience and safety of intrauterine devicescontinues to give hope that the IUD may one day provide an ideal methodfor worldwide population control, since it has been found,statistically, that intrauterine devices can provide effectivecontraception in a 93-99% range of effectivity, they do not requireconscious effort, are less subject to human failings than any other typeof contraceptive, their antifertility effect is completely reversible,they have minimal, if any systemic effect, and their effect is confinedessentially to the uterus. However, it is believed that even greaterantifertility effect can be achieved by utilizing other anticonceptionagents with an IUD, which agents do not have the serious detrimentalside effects noted above.

Consequently, there has been a need for improved medicated intrauterinedevices providing greater antifertility effect and in which the sideeffects of pain, metrorrhagia and/or menorrhagia are reduced oreliminated, and which are not associated with other serious side effectssuch as ectopic pregnancy.

While the inflammatory response of the endometrium to intrauterinedevices has heretofore been known, I have discovered that the chronicresponse of the endometrium to longterm intrauterine device exposure ismore a humoral type of reaction (accompanied by increased vascularpermeability with edema and interstitial hemorrhage) than theimmunologic or cellular type of response (accompanied by infiltration ofimmune complexes or of leukocytes, such as plasma cells or neutrophils).However, I have found that there are defects in small endometrialvessels which suggest damage caused by mechanical distortion of theuterine tissues. The defects generally lack hemostatic plugs ofplatelets and/or fibrin. Further, there is evidence that fibrinolysis isactivated in the uterus in response to the presence of an intrauterinedevice. This activation could result in blockage of normal hemostaticreaction at several levels in the coagulation system. Further, it mayinitiate, aid, or aggravate humoral inflammation by any one or all ofthe following mechanisms:

1. Activation of the complement system and histamine release;

2. Activation of prekallikrein; and

3. Release of fibrin degradation fragments.

Histamine can cause vascular dilation and increase vascularpermeability. Kallikrein (activated prekallikrein) releases bradykininwhich can have an effect similar to histamine and may also causecramping and pain. Fibrin degradation fragments may enhance the vasculareffects of histamine and bradykinin. Combined with distortion of theendometrium caused by myometrial contractility around the relativelyinelastic or unyielding IUD, which may also be associated with increasedprostaglandin synthesis and release, it may be predicted that excessivebleeding from leaky or broken vessels will occur. For these reasons,incorporation into medicated IUD devices of potent inhibitors ofplasminogen activation and plasmin activity (fibrinolytic activity) forthe purposes of intrauterine release over an extended time period canprovide an alleviation of the aforesaid undesired effects.

It has also heretofore been found that IUD associated uterine hemorrhagecan be alleviated by the systemic (oral) intake of the fibrinolyticinhibitors epsilon aminocaproic acid (EACA) and tranexamic acid. I havealso demonstrated that an EACA loaded IUD inserted into the uterus ofrhesus monkeys provides an ameliorative effect on menstrual blood loss,and there was no apparent systemic effect by such medicated devices onfibrinolytic activity in these animals. However, neither EACA nortranexamic acid would appear to be satisfactory agents for long-timeintrauterine medication. First, they are not highly potentanti-fibrinolytic agents and would have to be delivered at a rather highrate into the uterine cavity. Thus, a drug loaded IUD would becomeexhausted of its medication in a short period of time, or would requirean unacceptably large size of device. In addition, EACA and tranexamicacid are small molecules which are highly diffusible and water soluble.Therefore, intrauterine release thereof from a medicated intrauterinedevice at a steady, constant rate is difficult to control and effectiveconcentrations inside the uterus difficult to maintain. Consequently,inhibitor concentrations of either EACA and tranexamic acid of between1×10⁻³ and 1×10⁻⁴ Mol/liter, which is the concentratic of these drugsrequired to be effective, respectively, over a prolonged period of timeis generally not achievable considering the amount of medication whichis feasible to load into an IUD and considering the diffusion andsolubility properties of these compounds and the rate of water turnoverinside the uterus.

While there heretofore has been some indication that certain compoundsused for treatment of protozoal, bacterial and fungal infections mayhave anti-fibrinolytic properties, there has not heretofore been anyindication of anti-fertility action of these compounds added to anintrauterine device. These compounds may be generally defined as thearomatic amidines, and in particular, the aromatic diamidines. However,heretofore, it has not been specifically recognized that theiranti-fibrinolytic action inside the uterus can alleviate the IUD inducedmetrorrhagia and menorrhagia. Further, even though such metrorrhagia andmenorrhagia may be alleviated, the pain and cramps associated withintrauterine devices could still remain a major drawback to effectiveextensive use of medicated intrauterine devices as a population controltechnique.

In addition to the above-mentioned types of intrauterine devices, therehas also heretofore been provided intrauterine devices in which all or apart of the device is hollow and thus the device has walls defining thecavity. Such a device is shown, for example, in U.S. Pat. No. 3,896,819and other types of such devices are shown, for example, in U.S. Pat. No.3,710,795 in which the cavity is filled with a solid matrix, and otherprior art patents. Similarly, there have heretofore been proposedinflatable intrauterine devices in which the walls of the intrauterinedevice are flexible and it is inserted into the uterus in uninflatedcondition and subsequently expanded.

However, in none of the prior art devices has there heretofore beenprovided a drug releasable at a controlled rate over an extended periodof time which drug provides not only an antiproteolytic action but anenhanced contraceptive action. Accordingly, there has long been a needfor an intrauterine device which can provide the above desiderata.

Additionally, in many prior art IUDs, expulsion thereof is a somewhatfrequent occurrence. Such undesired expulsion is another drawback ofprior art IUDs.

Consequently, there has long been a need for a medicated intrauterinedevice which not only enhances the anti-fertility action of the IUD butalso provides reduction or elimination of metrorrhagia or menorrhagiafor an extended period of time, as well as decreasing the pain andcramps associated with wearing an intrauterine device, as well asdecreasing the tendency of expulsion thereof.

In my above mentioned co-pending patent applications Ser. Nos. 927,765,928,093, and 928,106 I have disclosed the structure associated with theuse of the amidines such as the aromatic and non-aromatic monoamidinesand diamidines for utilization in connection with an IUD to provide theabove desiderata. However, I have also discovered that the guanidines,such as aromatic monoguanidine, aromatic diguanidines, non-aromaticmonoguanidines and non-aromatic diguanidines also can provide the abovedesiderata.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide animproved intrauterine device.

It is another object of the present invention to provide an improvedmedicated intrauterine device of the type enhancing the anti-fertilityaction of the intrauterine device.

It is yet another object of the present invention to provide an improvedmedicated intrauterine device which reduces metrorrhagia andmenorrhagia.

It is yet another object of the present invention to provide an improvedintrauterine device that reduces pain and cramps associated with theutilization of an intrauterine device as well as minimizing theexpulsion thereof.

As set forth in my above mentioned co-pending patent applications Ser.Nos. 927,765, 928,093 and 928,106, the anti-proteolytic action and, inparticular, the anti-fibrinolytic action of the aromatic monoamidines,aromatic diamidines and non-aromatic diamidines can provide a reductionin metrorrhagia and menorrhagia because of the particularcharacteristics associated with the reaction of the endometrium and/orthe fluid of the uterus to the presence of an intrauterine device.Further, it is believed that inhibition of other proteolytic systems inthe endometrium and/or muscle wall of the uterus can reduce and/oreliminate the pain and cramps associated with wearing an intrauterinedevice, as well as minimizing the risk of expulsion thereof. Theamidines and, in particular, the aromatic monoamidines, aromaticdiamidines, and non-aromatic diamidines, have been found to possess thedesired properties, due to the anti-fibrinolytic and otheranti-proteolytic effect thereof, to reduce or eliminate metrorrhagiaand/or menorrhagia.

There has not, heretofore, been any recognition that the guanidines havean anti-proteolytic action, and an anti-fibrinolytic action in theuterus, or an anti-bleeding action, or an anti-fertility action. I havediscovered, however, that the guanidines, in addition to the amidines,do have such properties and, it is believed, may have even more potenteffects.

Thus, I have discovered that there is a surprising and unexpect resultin utilization of guanidines with intrauterine devices in that they maydecrease IUD induced uterine bleeding and enhance the anti-fertilityeffect of the IUD by providing an anti-proteolytic and, particularly, ananti-fibrinolytic action in the uterus. Each treated IUD, therefore,may, additionally, cause a greater contraceptive effect than hasheretofore been obtainable with the above-mentioned prior art IUDs ofeither the plain or medicated type. This unexpected result, it isbelieved, is achieved by the mechanism of the guanidine action upon thefertilized egg or the blastocyst (preimplantation embryo) to cause it todegenerate. The guanidine could, in addition, act on the sperm to eitherkill or render them ineffective in fertilization.

Further, it is believed, that certain anti-proteolytic action of theguanidines could reduce or eliminate the pain and cramps oftenassociated with wearing an IUD.

In the present invention, the IUD is in the form of a uterus insertablebody member having first walls defining a cavity therein. The cavity mayextend throughout the IUD or only for a portion thereof. Further, thewalls defining the cavity may be semi-rigid or flexible. In the flexiblewalled IUD, the IUD may be inserted into the uterus in an uninflatedcondition and then subsequently expanded by filling with the solutioncontaining the required concentration of the drug. The walls definingthe cavity are permeable to the drug. The drug, which may be one or moredrugs selected from the class consisting of aromatic monoguanidines,aromatic diguanidines, non-aromatic monoguanidines and non-aromaticdiguanidines, or a mixture of one or more guanidines with one or moreamidines, is provided within the cavity. The permeability of the wallsdefining the cavity allows a predetermined, controlled release rate ofthe drug to the uterus. The term "drug" as utilized herein refers toeither a single one of the above-mentioned guanidines, or a mixture ofmore than one guanidines with one or more of the amidines as set forthin my co-pending patent applications Ser. Nos. 927,765, 928,093 and928,106. In addition, if desired, a coating of the drug may also beprovided on some or all of the external surface of the body member. Thecoating may be covalently bonded to the surface of the body member andconsists of a non-biodegradable monomer, dimer, oligomer, orcross-linked polymer of the drug. Such embodiment provides a prolongedsurface effect for reducing deleterious effects on the uterine wall, aswell as provides the desired prolonged release of the drug from the bodymember. The bleeding of the endometrium in contact with the intrauterinedevice is at the surface of the endometrium. The inhibition ofplasminogen activator and plasmin by solid phase enzyme inhibitors suchas the surface linked drugs described in this paragraph constantlyduring the wearing of the intrauterine device could lead to a lesseningof the bleeding at the interface between the endometrium and theintrauterine device.

In another embodiment of the present invention, the surface of the bodymember of any one of the above-defined embodiments may be partiallycovered by metallic copper to provide additional anti-conceptive actionfor the device.

The drug may be utilized either in its base form, or as certain esterssuch as isethionate, or as certain salts, such as hydrochloride orphosphate, depending upon the degree of solubility desired in theuterine fluid for control of release rate and tissue uptake of the drug,as well as enhancing the effectiveness of the particular compoundemployed.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other embodiments of the present invention may be morefully understood from the following detailed description taken togetherwith the accompanying drawing wherein similar reference characters referto similar elements throughout and in which:

FIGS. 1 and 1A illustrate embodiments of an intrauterine device usefulin the practice of the invention;

FIG. 2 illustrates another embodiment of an intrauterine device usefulin the practice of the present invention;

FIG. 3 illustrates another embodiment of an intrauterine device usefulin the practice of the present invention;

FIG. 4 illustrates another embodiment of an intrauterine device usefulin the practice of the present invention; and

FIG. 5 illustrates another embodiment of an intrauterine device usefulin the practice of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The group of preselected compounds of the present invention are theguanidines and in particular the aromatic monoguanidines, the aromaticdiguanidines, and non-aromatic monoguanidines, and the non-aromaticdiguanidines. The aromatic guanidines may be an aromatic monoguanidineof the general formula: ##STR1## wherein: R is a carbon chain with orwithout other elements (such as hydrogen, nitrogen, oxygen, sulfer,etc.); an aromatic group (such as benzene) with or without additionalcarbons, carbon chains, and other elements; a cyclic non-aromatic group(such as cyclohexane) with or without additional carbons, carbon chains,and other elements; or any of the above in combination; and ##STR2##represents the benzene ring.

As prepared for utilization in the invention herein, there may beutilized an aromatic diguanidine of the general formula: ##STR3## inwhich each guanidine group: ##STR4## may be substituted in either a metaor para position with respect to R₁, and wherein:

R₁ is generally a hydro carbon chain with or without ether or esterbonds to the benzene rings;

R₂ and R₃ can be hydrogen, chlorine, bromine, iodine, hydroxyl group,alkyl, or other group; and ##STR5## represents the benzene ring.

It is understood that the series of examples of aromatic diamidines inTable I, below, will also exemplify the aromatic diguanidines in everyrespect except that for the latter class of compounds guanidino groups:##STR6## are substituted for amidino groups: ##STR7## Two examples ofaromatic monoguanidines are the following ##STR8##ethyl-p-guanidinobenzoate and ##STR9##p-nitrophenyl-p'-guanidinobenzoate (commonly named NPGB). Two examplesof aromatic diguanidines are the following: ##STR10##p-guanidinophenyl-p'guanidinobenzoate and ##STR11## 1,3 bis(2-bromo-4-guanidinophenoxy) propane. [This last compound is analogousto dibromopropamidine (Table I) except that it is a diguanidine ratherthan a diamidine by virtue of the two guanidino groups: ##STR12## atboth extremities of the molecule in place of the two amidino groups:##STR13## This diguanidine is assigned a chemical name in thisapplication rather than a common or trivial name (such as"dibromopropaguanidine") because the compound and its analogs are not incommon use and have not been previously given common names in thescientific literature.]

The non-aromatic guanidines may be a non-aromatic monoguanidine of thegeneral formula: ##STR14## wherein R may represent a carbon chain withor without other elements (such as hydrogen, nitrogen, oxygen, sulfer,etc.); a cyclic non-aromatic group (such as cyclohexane) with or withoutadditional carbons, carbon chains, and other elements; or any of theabove in combination.

As preferred for utilization in the invention herein, there may beutilized a non-aromatic diguanidine of the general formula: ##STR15##wherein: R may represent a carbon chain with or without other elements(such as hydrogen, nitrogen, oxygen, sulfur, etc.); a cyclicnon-aromatic group (such as cyclohexane) with or without additionalcarbons, carbon chains, and other elements; or any of the above incombination.

An example of a non-aromatic monoguanidine is the following: ##STR16##guanidiniocyclohexane. An example of a non-aromatic diguanidine is thefollowing: ##STR17## 1,4-di(2-guanidinovinyl)cyclohexane.

In the above, ##STR18## represents cyclohexane

As set forth in my co-pending patent applications--Ser. Nos. 927,765,928,093, and 928,106, Table I below lists particular aromatic diamidinesuseful in the practice of the inventions set forth therein, and usefulin the practice of certain embodiments of the present invention whereinan amidine, such as the diamidines of Table I, are mixed with one ormore guanidines to provide the drug of the present invention.

                  TABLE I                                                         ______________________________________                                        AROMATIC DIAMIDINES                                                                                                 Relative                                Drug Name      R.sub.1 Carbon Chain                                                                       R.sub.2                                                                             R.sub.3                                                                           Potency                                 ______________________________________                                        Dibromopropamidine                                                                           C.sub.3 H.sub.6                                                                            Br    Br  1.0                                     Phenamidine    --           H     H   0.2                                     Octamidine     C.sub.8 H.sub.16                                                                           H     H   2.6                                     m-Pentamidine  C.sub.5 H.sub.10                                                                           H     H   0.6                                     Hexamidine     C.sub.6 H.sub.12                                                                           H     H   1.6                                     Dichlorohexamidine                                                                           C.sub.6 H.sub.12                                                                           Cl    Cl  1.9                                     Pentamidine    C.sub.5 H.sub.10                                                                           H     H   2.4                                     Monoiodohexamidine                                                                           C.sub.6 H.sub.12                                                                           I     H   4.4                                     Dibromopentamidine                                                                           C.sub.5 H.sub.10                                                                           Br    Br  3.6                                     Propamidine    C.sub.3 H.sub.6                                                                            H     H   1.2                                     Heptamidine    C.sub.7 H.sub.14                                                                           H     H   1.9                                     Diiodopentamidine                                                                            C.sub.5 H.sub.10                                                                           I     I   6.8                                     Diiodohexamidine                                                                             C.sub.6 H.sub.12                                                                           I     I   7.5                                     Butamidine     C.sub.4 H.sub.8                                                                            H     H                                           Monochloropropamidine                                                                        C.sub.3 H.sub.6                                                                            Cl    H                                           Monochlorobutamidine                                                                         C.sub.4 H.sub.8                                                                            Cl    H                                           Monochloropentamidine                                                                        C.sub.5 H.sub.10                                                                           Cl    H                                           Monochlorohexamidine                                                                         C.sub.6 H.sub.12                                                                           Cl    H                                           Monochloroheptamidine                                                                        C.sub.7 H.sub.14                                                                           Cl    H                                           Monochloroctamidine                                                                          C.sub.8 H.sub.16                                                                           Cl    H                                           Monochlorononamidine                                                                         C.sub.9 H.sub.18                                                                           Cl    H                                           Monobromopropamidine                                                                         C.sub.3 H.sub.6                                                                            Br    H                                           Monobromobutamidine                                                                          C.sub.4 H.sub.8                                                                            Br    H                                           Monobromopentamidine                                                                         C.sub.5 H.sub.10                                                                           Br    H                                           Monobromohexamidine                                                                          C.sub.6 H.sub.12                                                                           Br    H                                           Monobromoheptamidine                                                                         C.sub.7 H.sub.14                                                                           Br    H                                           Monobromoctamidine                                                                           C.sub.8 H.sub.16                                                                           Br    H                                           Monobromononamidine                                                                          C.sub.9 H.sub.18                                                                           Br    H                                           Moniodopropamidine                                                                           C.sub.3 H.sub.6                                                                            I     H                                           Monoidobutamidine                                                                            C.sub.4 H.sub.6                                                                            I     H                                           Monoiodopentamidine                                                                          C.sub.5 H.sub.10                                                                           I     H                                           Monoiodohexamidine                                                                           C.sub.6 H.sub.12                                                                           I     H                                           Monoiodoheptamidine                                                                          C.sub.7 H.sub.14                                                                           I     H                                           Monoiodoctamidine                                                                            C.sub.8 H.sub.16                                                                           I     H                                           Monoiodononamidine                                                                           C.sub.9 H.sub.18                                                                           I     H                                           Dichloropropamidine                                                                          C.sub.3 H.sub.6                                                                            Cl    Cl                                          Dichlorobutamidine                                                                           C.sub.4 H.sub.8                                                                            Cl    Cl                                          Dichloropentamidine                                                                          C.sub.5 H.sub.10                                                                           Cl    Cl                                          Dichlorohexamidine                                                                           C.sub.6 H.sub.12                                                                           Cl    Cl                                          Dichloroheptamidine                                                                          C.sub.7 H.sub.14                                                                           Cl    Cl                                          Dichloroctamidine                                                                            C.sub.5 H.sub.16                                                                           Cl    Cl                                          Dichlorononamidine                                                                           C.sub.9 H.sub.19                                                                           Cl    Cl                                          Dibromopropamidine                                                                           C.sub.3 H.sub.6                                                                            Br    Br                                          (already listed)                                                              Dibromobutamidine                                                                            C.sub.4 H.sub.8                                                                            Br    Br                                          Dibromopentamidine                                                                           C.sub.5 H.sub.10                                                                           Br    Br                                          Dibromohexamidine                                                                            C.sub.6 H.sub.12                                                                           Br    Br                                          Dibromoheptamidine                                                                           C.sub.7 H.sub.14                                                                           Br    Br                                          Dibromoctamidine                                                                             C.sub.8 H.sub.16                                                                           Br    Br                                          Dibromononamidine                                                                            C.sub.9 H.sub.18                                                                           Br    Br                                          Diiodopropamidine                                                                            C.sub.3 H.sub.6                                                                            I     I                                           Diiodobutamidine                                                                             C.sub. 4 H.sub.8                                                                           I     I                                           Diiodopentamidine                                                                            C.sub.5 H.sub.10                                                                           I     I                                           Dioodohexamidine                                                                             C.sub.6 H.sub.12                                                                           I     I                                           Diiodoheptamidine                                                                            C.sub.7 H.sub.14                                                                           I     I                                           Diiodooctamidine                                                                             C.sub.8 H.sub.16                                                                           I     I                                           Diiodononamidine                                                                             C.sub.9 H.sub.18                                                                           I     I                                           Monochloromonobromo-                                                                         C.sub.3 H.sub.6                                                                            Cl    Br                                          propamidine                                                                   Monochloromonobromo-                                                                         C.sub.4 H.sub.8                                                                            Cl    Br                                          butamidine                                                                    Monochloromonobromo-                                                                         C.sub.5 H.sub.10                                                                           Cl    Br                                          pentamidine                                                                   Monochloromonobromo-                                                                         C.sub.6 H.sub.12                                                                           Cl    Br                                          hexamidine                                                                    Monochloromonobromo-                                                                         C.sub.7 H.sub.14                                                                           Cl    Br                                          heptamidine                                                                   Monochloromonobromo-                                                                         C.sub.8 H.sub.16                                                                           Cl    Br                                          octamidine                                                                    Monochloromonobromo-                                                                         C.sub.9 H.sub.18                                                                           Cl    Br                                          nonamidine                                                                    Monochloromonoiodo-                                                                          C.sub.3 H.sub.6                                                                            Cl    I                                           propamidine                                                                   Monochloromonoiodo-                                                                          C.sub.4 H.sub.8                                                                            Cl    I                                           butamidine                                                                    Monochloromonoido-                                                                           C.sub.5 H.sub.10                                                                           Cl    I                                           pentamidine                                                                   Monochloromonoiodo-                                                                          C.sub.6 H.sub.12                                                                           Cl    I                                           hexamidine                                                                    Monochloromonoiido-                                                                          C.sub.7 H.sub.14                                                                           Cl    I                                           heptamidine                                                                   Monochloromonoiodo-                                                                          C.sub.8 H.sub.16                                                                           Cl    I                                           octamidine                                                                    Monochloromonoiodo-                                                                          C.sub.9 H.sub.18                                                                           Cl    I                                           nonamidine                                                                    Monobromomonoiodo-                                                                           C.sub.3 H.sub.6                                                                            Br    I                                           propamidine                                                                   Monobromomonoiodo-                                                                           C.sub.4 H.sub.8                                                                            Br    I                                           butamidine                                                                    Monobromomonoiodo-                                                                           C.sub.5 H.sub.10                                                                           Br    I                                           pentamidine                                                                   Monobromomonoiodo-                                                                           C.sub.6 H.sub.12                                                                           Br    I                                           hexamidine                                                                    Monobromomonoido-                                                                            C.sub.7 H.sub.14                                                                           Br    I                                           heptamidine                                                                   Monobromomonoiodo-                                                                           C.sub.8 H.sub.16                                                                           Br    I                                           octamidine                                                                    Monobromomonoiodo-                                                                           C.sub.9 H.sub.18                                                                           Br    I                                           nonamidine                                                                    ______________________________________                                    

In addition to the aromatic diguanidines, which, as noted above, aresimilar to the aromatic diamidines listed in Table I except for thesubstitution of the guanidine group for the amidine group in the drugand which, when trivial names have been assigned thereto will havetrivial names similar to those shown in Table I, other aromaticdiguanidines, aromatic monoguanidines, non-aromatic monoguanidines andnon-aromatic diguanidines may also be utilized in accordance with theprinciples of the present invention.

The relative potency shown in Table I is expressed in relationship todibromopropamidine, which has been discovered to be a highly potentfibrinolytic inhibitor. The numerical values are expressed as areciprocal of the concentration of the drug producing the equivalentinhibition to the dibromopropamidine. Where no values for relativepotency are listed such values have not been specifically determined.

The exact relative potency for the guanidines of the present inventionhas not yet been completely determined. However, those skilled in theart may rapidly determine the relative potency for any particularguanidine selected.

Referring now to the drawing, there are illustrated in FIGS. 1 through 5thereof various forms of IUDs useful in the practice of the presentinvention. According to the principles of the present invention many ofthe forms shown in FIGS. 1 through 5, as well as many other geometricalconfigurations of IUDs may be utilized in the practice of the presentinvention. Thus, the illustration of the IUDs illustrated in FIGS. 1through 5 herein is not limiting to the principles of the practice ofthe present invention.

In the embodiment 10 of the intrauterine device shown in FIG. 1 it isgenerally comprised of a body member 12 having first walls 14 defining afluid receiving cavity 16. In the embodiment 10 the first walls 14 areof a semi-flexible nature and are fabricated of, for example, thepolymer of: 1. low density polyethylene or 2. Polyethyl vinyl acetate.In the embodiment 10, as can be seen, the cavity 16 is substantiallycoextensive with the first walls 14.

Contained within the cavity 16 is a concentrated fluid solution of thedrug. The drug may be in a concentrated aqueous or organic ornon-organic hydrophobic solution 18 within the cavity 16. The solutionwould be in a concentration range from 50 to 200 milligrams permilliliter or approximately 5 to 20% by weight. Additionally, the drugmay also be provided in the form of a suspension.

Specifically, in the embodiment 10 shown in FIG. 1, wherein the wall 14of the body member are semi-flexible, the drug could be provided in acrystalline form in the cavity 16 either with or without a solvent andin the range of 10 to 50% by weight. Further, instead of the crystallineform of the drug, the drug may consist of a concentrated paste with aminimal amount of solvent sufficient to provide the desired viscosityand/or consistency and providing the abovedescribed concentration level.With the wall 14 of the body member 12 fabricated from theabove-mentioned materials, the walls 14 are permeable to the drugcontained within the cavity 16

FIG. 1A illustrates another embodiment of the present inventiongenerally designated 10' which is generally similar to the embodiment 10of FIG. 1. However, in the embodiment 10', the cavity 16 is notcoextensive with the first walls 14 but only extends in the regiondefined by the walls 14a. The walls 14' define the remainder of the bodymember 12 and no cavity is provided in this area. The concentrated fluidsolution of the drug 18 is contained only within the cavity 16.

It will be appreciated, of course, that as utilized herein the term"concentrated fluid solution of the drug" also defines a concentratedfluid suspension of the drug.

In another embodiment of the present invention generally designated 20as shown in FIG. 2, the IUD generally designated 12 having first walls21 defining a cavity 16 in the upper portion 12a of the IUD 12. Thefirst walls 20 are flexible walls and the upper portion 20a, inapplication, may be inserted into the uterus with the lower portion 12bof the body member 12 extending through the uterus, e.g., through theuterine cervical canal, to regions external to the uterus, e.g. thevagina. When inserted, the first walls 20 are collapsed so that it maybe passed through the cervical canal into the uterine cavity. Afterinsertion into the uterine cavity the cavity of the device 16 may befilled, thereby inflating the first wall 20 and cavity 16, and thedevice is thus filled with a concentrated solution of the drug generallydesignated 18. In this, and in the embodiments 30, 40 and 50 shown,respectively, in FIGS. 3, 4 and 5, the drug is provided in the form ofthe concentrated solution described above in connection with theembodiment 10 shown in FIG. 1. After the cavity 16 has been filled tothe desired volume with the concentrated solution of the drug, theportion 12b of the body member 12 extending external to the uterus maybe suitably sealed, for example, by tying a knot therein and the IUDleft in place in the uterus for the desired time period. The embodiments30, 40 and 50 shown in FIGS. 3, 4 and 5, respectively, are generallysimilar to the embodiment 21 shown in FIG. 2 except that the shape ofthe upper portion 12a of the body member 12 is provided in differentshapes or configurations. That is, in embodiment 30 of FIG. 3 the upperportion 12a is in the form of a "top", in the embodiment 40 of FIG. 4the upper portion 12a is in a spherical form. In the embodiment 50 ofFIG. 5 the upper portion 12a is in an ovoid form. It will be appreciatedthat many other shapes may be provided for the upper portion 12a.

In the IUDs shown in FIGS. 1 through 5, the drug may, in addition tobeing provided in the cavity 16, also be provided in the walls 14 ofFIG. 1 or walls 20 of FIGS. 2 through 5, and/or on the outer surface 14aor 20a thereof. Accordingly, the drug may be in a simple mixture withthe polymer matrix defining the walls 14 or 20. The shape, charge, andother characteristics of the drug molecule such as its hydrophobicity,as well as similar characteristics of the polymer matrix of the walls 14and 20 may be varied as desired to select the particular release rate ofthe drug from the walls of 14 and 20 to provide the desired totalrelease rate of the drug into the intrauterine cavity when consideringthe release rate of the drug from the solution 18.

The ratio of the mixture of the drug contained within the walls 14 or 20may be on the order of, for example, 10% to 50% by weight depending uponthe potency of the drug and the particular polymer matrix from which thebody member 12 is fabricated.

The drug may also be provided as a biodegradable polymer or copolymerand mixed into the walls 14 and 20 with selections of characteristicsand ratios of weight as above defined.

The drug may also be provided in the biodegradable polymer or copolymerform and covalently bonded with the polymer matrix of the walls 14 or 20of the body member 12 either within the walls or on the surface thereof.

Further, a biodegradable cross-linked polymer or copolymer coating ofthe drug bonded covalently to the outer surface 14a or 20a of the bodymember 12 to provide a soft hydrogel coating thereover. Such a coatingis likely to be particularly effective in aiding retention of the IUD inthe uterus during the time period soon after insertion thereof. Thecoating may be provided over all or part of the external surface 14a or20a. The characteristics of the coating may be selected to provide thedesired release rate of the drug into the uterine cavity when consideredwith the release of the drug from the solution 18 described above, ormay be selected to provide specific additional release rates in certainportions thereof such as those in contact with the walls of the uterus.

Further, the drug may also be provided in a non-biodegradable monomer,dimer or olymer or a cross-linked polymer on the outer surface 14a or20a of the body member 12. This coating may be provided by covalent orother chemical bonding between the drug molecules and the outer surface14a or 20a. Since the bleeding of the endometrium is at the interfacebetween the endometrium and the IUD, the solid phase enzyme inhibitionprovided by the drug at the point of contact between the endometrium andthe IUD can reduce the bleeding associated with utilization of an IUD.

Further, since, as noted above, copper release has also provenanti-conceptive in IUDs, a portion of the outer surface 14a or 20a maybe provided with a coating of metallic copper such as a thin wire,copper plating, or the like.

It has been found that the drugs according to the present inventionquite unexpectedly may also provide an anti-conceptive effect. It isbelieved that this effect, which should enhance the anti-conceptiveeffect of the intrauterine device itself, is due to the activity of thedrug and its action on the very early embryo and possibly on the sperm.

Further, it is believed yet an additional unexpected and surprisingresult may be obtained due to the anti-proteolytic action of the drug.This effect is a reduction in the pain and/or cramps and expulsionheretofore associated with utilization of intrauterine devices includingmedicated IUDs.

The range of concentrations necessary to provide the desired effectsmentioned above depend, of course, upon the particular drug orcombinations selected. For example, as noted in my copending patentapplications, Ser. Nos. 927,765, 928,093, and 928,106, fordibromopropamidine introduced into the uterine cavity and endometrialtissue water, and with an endometrial water turnover rate of 200milliliters per day and with complete distribution of the drug in theendometrial water turned over, an intrauterine release rate of 50 to 200mcg per day would be expected to produce a concentration ofdibromopropamidine in the range of 0.5 to 2.0×10⁻⁶ moles per liter inendometrial water. Since, in general, there will be less than completedistribution of the drug into the endometrial water turned over eachday, the concentration of the drug in the uterine cavity could reachmuch higher levels, for example, on the order of 10⁻⁶ to 10⁻⁴ moles perliter. This concentration range is sufficient to provide both theantifibrinolytic effects, as well as the anti-conceptive orantifertility effects desired, and, also, it is believed, the reductionin pain, cramps and expulsion. With the above release rate (50-200 mcgper day), the known sizes of intrauterine devices currently available,and the amount of drug which can be incorporated into such devices, aneffective life span of, for example, at least one to three years can beprovided for such medicated devices.

The concentration of the drug in the solution, which may be aconcentrated aqueous or organic or non-organic hydrophobic solution,contained within the cavity of an inflatable IUD would range from 50 mg,or less, to 200 mg per ml (5% to 20% by weight). As noted, this may be asolution or suspension. The concentration required in a hollow coredevice would range from about 10%, or less, to about 50% by weight andwould consist of the crystalline form of the drug packed into the hollowcore without solvent, or consist of a highly concentrated paste of thedrug with minimal solvent.

At least one aromatic guanidine, NPGB as identified above, has ananti-fibrinolytic effect on the order of 100 times greater than that ofdibromopropamidine (on a molar concentration basis). As little as 0.5 to2.0 mcg per day release of NPGB from a medicated IUD according to theprinciples of the present invention may be satisfactorily effective.Thus, the estimated range of daily release of the drug according to thepresent invention from a medicated IUD may be as low as, for example,0.5 mcg to as high as 200 mcg, depending upon the particularconstituents selected for inclusion in the drug. The useful life span ofa device releasing, for example, 0.5 mcg per day may greatly exceedthree years.

Those skilled in the art, of course, can readily determine theappropriate release rate desired for any drug or combination thereofwhich may be utilized according to the principles of the presentinvention and, in accordance with known principles, establish thedesired release rate thereof to achieve effectiveness

Further, those skilled in the art may find many variations andadaptations of the present invention and all such variations andadaptations thereof falling within the scope and spirit of the inventionare covered by the appended claims.

I claim:
 1. In an intrauterine device of the type insertable in theuterus and having a surface contacting the uterus and first wallsdefining a fluid-receiving cavity in at least a portion thereof, theimprovement comprising, in combination:one of a concentrated fluidsolution and suspension of at least one drug in said cavity and said atleast one drug of the type providing an antifibrinolytic, a reversibleantifertility, and an antiproteolytic effect; and said first walls ofsaid intrauterine device comprising a polymer having a predeterminedpermeability to said at least one drug; said at least one drug comprisesat least a guanidine, and whereby, said predetermined permeability ofsaid first walls controls the release rate of said drug from saidcavity.
 2. The arrangement defined in claim 1 wherein: said first wallsare semi-flexible.
 3. The arrangement defined in claim 1 wherein: saidfirst walls define an inflatable cavity.
 4. The arrangement defined inclaim 1 wherein:said at least one drug is selected from the classconsisting of:(a) a mixture of an amidine and a guanidine; (b) a mixtureof more than one amidine and a guanidine; (c) a mixture of an amidineand more than one guanidine; (d) a mixture of more than one amidine andmore than one guanidine; (e) a guanidine; and (f) a mixture of more thanone guanidine.
 5. The arrangement defined in claim 1 wherein:saidguanidine of said at least one drug is selected from the classconsisting of:(a) aromatic monoguanidines; (b) aromatic diguanidines;(c) non-aromatic monoguanidines; and (d) non-aromatic diguanidines. 6.The arrangement defined in claim 1 wherein:said at least one drug isselected from the class of aromatic monoguanidines of the group:##STR19## wherein R is selected from the class consisting of: (a) acarbon chain free of other elements;(b) a carbon chain with at least oneother element; (c) an aromatic group free of additional carbon atoms,carbon chains and other elements; (d) an aromatic group with at leastone addition selected from the class consisting of carbon atoms, carbonchains and other elements; (e) a cyclic non-aromatic group free ofadditional carbon atoms, carbon chains and other elements; (f) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains, and other elements; and (g) acombination of at least two of (a), (b), (c), (d), (e) and (f);andwherein: ##STR20## represents the benzene ring.
 7. The arrangementdefined in claim 1 wherein:said at least one drug is selected from theclass of aromatic diguanidines of the group: ##STR21## and wherein eachguanidine group ##STR22## is in one of a meta or para position withrespect to R₁, and in which: R₁ is selected from the class consistingof:(a) a hydrocarbon chain free of ether and ester bonds to the benzenering; and (b) a hydrocarbon chain having at least one bond selected fromthe class of ether bonds and ester bonds to the benzene ring; R₂ and R₃are selected from the class consisting of:hydrogen, chlorine, bromine,iodine, hydroxyl group and alkyl group; and ##STR23## represents thebenzene ring.
 8. The arrangement defined in claim 1 wherein:said atleast one drug is selected from the class of nonaromatic monoguanidinesof the group: ##STR24## wherein R is selected from the class consistingof: (a) a carbon chain free of other elements; (b) a carbon chain withat least one other element; (c) a cyclic non-aromatic group free ofadditional carbon atoms, carbon chains and other elements; (d) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains and other elements; (e) acombination of at least two of (a), (b), (c), and (d).
 9. Thearrangement defined in claim 1 wherein:said at least one drug isselected from the class consisting of non-aromatic diguanidines of thegroup: ##STR25## wherein R is selected from the class consisting of: (a)a carbon chain free of other elements; (b) a carbon chain with at leastone other element; (c) a cyclic non-aromatic group free of additionalcarbon atoms, carbon chains and other elements;(d) a cyclic non-aromaticgroup with at least one addition selected from the class consisting ofcarbon atoms, carbon chains and other elements; (e) a combination of atleast two of (a), (b), (c), and (d).
 10. The arrangement defined inclaim 1 wherein said at least one drug is selected from the classconsisting of: ##STR26##
 11. The arrangement defined in claim 1 andfurther comprising:a coating on at least a portion of said surface ofsaid intrauterine device, and said coating comprising one of abiodegradable cross-linked polymer and co-polymer of a second drug, andsaid second drug comprises at least a guanidine, and said second drugchemically bonded to said first portion of said surface.
 12. Thearrangement defined in claim 11 wherein:said second drug furthercomprises a soft hydrogel coating.
 13. The arrangement defined in claim11 wherein:said second drug is selected from the class consisting of:(a)a mixture of an amidine and a guanidine; (b) a mixture of more than oneamidine and a guanidine;(c) a mixture of an amidine and more than oneguanidine; (d) a mixture of more than one amidine and more than oneguanidine; (e) a guanidine; and (f) a mixture of more than oneguanidine.
 14. The arrangement defined in claim 11 wherein:saidguanidine of said at least one drug is selected from the classconsisting of:(a) aromatic monoguanidines; (b) aromatic diguanidines;(c) non-aromatic monoguanidines; and (d) non-aromatic diguanidines. 15.The arrangement defined in claim 11 wherein:said at least a guanidine ofsaid second drug is selected from the class consisting of aromaticmonoguanidines of the group: ##STR27## wherein R is selected from theclass consisting of: (a) a carbon chain free of other elements;(b) acarbon chain with at least one other element; (c) an aromatic group freeof additional carbon atoms, carbon chains and other elements;(d) anaromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains and other elements; (e) acyclic non-aromatic group free of additional carbon atoms, carbon chainsand other elements; (f) a cyclic non-aromatic group with at least oneaddition selected from the class consisting of carbon atoms, carbonchains, and other elements; and (g) a combination of at least two of(a), (b), (c), (d), (e) and (f); and wherein: ##STR28## represents thebenzene ring.
 16. The arrangement defined in claim 11 wherein:said atleast a guanidine of said second drug is selected from the classconsisting of aromatic diguanidines of the group: ##STR29## and whereineach guanidine group ##STR30## is in one of a meta or para position withrespect to R₁, and in which: R₁ is selected from the class consistingof:(a) a hydrocarbon chain free of ether and ester bonds to the benzenering; and (b) a hydrocarbon chain free of ether and ester bonds selectedfrom the class of ether bonds and ester bonds to the benzene ring; R₂and R₃ are selected from the class consisting of:hydrogen, chlorine,bromine, iodine, hydroxyl group and alkyl group; and ##STR31##represents the benzene ring.
 17. The arrangement defined in claim 11wherein said at least a guanidine of said second drug is selected fromthe class consisting of non-aromatic monoguanidines of the group:##STR32## wherein R is selected from the class consisting of : (a) acarbon chain free of other elements;(b) a carbon chain with at least oneother element; (c) a cyclic non-aromatic group free of additional carbonatoms, carbon chains and other elements; (d) a cyclic non-aromatic groupwith at least one addition selected from the class consisting of carbonatoms, carbon chains and other elements; (e) a combination of at leasttwo of (a), (b), (c), and (d).
 18. The arrangement defined in claim 11wherein:said at least a guandine of said second drug is selected fromthe class consisting of the group: ##STR33## wherein R is selected fromthe class consisting of: (a) a carbon chain free of other elements;(b) acarbon chain with at least one other element; (c) a cyclic non-aromaticgroup free of additional carbon atoms, carbon chains and other elements;(d) a cyclic non-aromatic group with at least one addition selected fromthe class consisting of carbon atoms, carbon chains and other elements;(e) a combination of at least two of (a), (b), (c), and (d).
 19. Thearrangement defined in claim 11 wherein:said at least a guanidine ofsaid second drug is selected from the class consisting of the group:##STR34##
 20. The arrangement defined in claim 1 and furthercomprising:a coating on at least a first portion of said surface of saidintrauterine device, and said coating comprising one of anon-biodegradable monomer, dimer, oligomer and cross-linked polymer of asecond drug, and said second drug comprises at least a guanidine. 21.The arrangement defined in claim 15 wherein:said second drug is selectedfrom the class consisting of:(a) a mixture of an amidine and aguanidine; (b) a mixture of more than one amidine and a guanidine; (c) amixture of an amidine and more than one guanidine; (d) a mixture of morethan one amidine and more than one guanidine; (e) a guanidine; and (f) amixture of more than one guanidine.
 22. The arrangement defined in claim15 and further comprising:said guanidine of said at least one drug isselected from the class consisting of:(a) aromatic monoguanidines; (b)aromatic diguanidines; (c) non-aromatic monoguanidines; and (d)non-aromatic diguanidines.
 23. The arrangement defined in claim 15wherein:said at least a guanidine of said second drug is selected fromthe class consisting of aromatic monoguanidines of the group: ##STR35##wherein R is selected from the class consisting of: (a) a carbon chainfree of other elements;(b) a carbon chain with at least one otherelement; (c) an aromatic group free of additional carbon atoms, carbonchains and other elements;(d) an aromatic group with at least oneaddition selected from the class consisting of carbon atoms, carbonchains and other elements; (e) a cyclic non-aromatic group free ofadditional carbon atoms, carbon chains and other elements; (f) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains, and other elements; and (g) acombination of at least two of (a), (b), (c), (d), (e) and (f); and##STR36## represents the benzene ring.
 24. The arrangement defined inclaim 11 wherein:said at least a guanidine of said second drug isselected from the class consisting of aromatic diguanidines of thegroup: ##STR37## and wherein each guanidine group ##STR38## is in one ofa meta or para position with respect to R₁, and in which: R₁ is selectedfrom the class consisting of:(a) a hydrocarbon chain free of ether andester bonds to the benzene ring; and (b) a hydrocarbon chain free ofether and ester bonds selected from the class of ether bonds and esterbonds to the benzene ring; R₂ and R₃ are selected from the classconsisting of:hydrogen, chlorine, bromine, iodine, hydroxyl group andalkyl group; and ##STR39## represents the benzene ring.
 25. Thearrangement defined in claim 15 wherein said at least a guanidine ofsaid second drug is selected from the class consisting of non-aromaticmonoguanidines of the group: ##STR40## wherein R is selected from theclass consisting of: (a) a carbon chain free of other elements;(b) acarbon chain with at least one other element; (c) a cyclic non-aromaticgroup free of additional carbon atoms, carbon chains and other elements;(d) a cyclic non-aromatic group with at least one addition selected fromthe class consisting of carbon atoms, carbon chains and other elements;(e) a combination of at least two of (a), (b), (c), and (d).
 26. Thearrangement defined in claim 15 wherein:said at least a guanidine ofsaid second drug is selected from the class consisting of the group:##STR41## wherein R is selected from the class consisting of: (a) acarbon chain free of other elements;(b) a carbon chain with at least oneother element; (c) a cyclic non-aromatic group free of additional carbonatoms, carbon chains and other elements; (d) a cyclic non-aromatic groupwith at least one addition selected from the class consisting of carbonatoms, carbon chains and other elements; (e) a combination of at leasttwo of (a), (b), (c), and (d).
 27. The arrangement defined in claim 15wherein:said at least a guanidine of said second drug is selected fromthe class consisting of the group: ##STR42##
 28. The arrangement definedin claim 11 further comprising: a coating of copper on a second portionof said surface.
 29. The arrangement defined in claim 15 furthercomprising: a coating of copper on a second portion of said surface. 30.In an intrauterine device of the type insertable in the uterus andhaving a surface contacting the uterus and first walls defining a fluidreceiving cavity in at least a portion thereof, the improvementcomprising, in combination:one of a crystalline form and a paste form ofat least one drug in said cavity and said drug of the type providing ananti-fibrinolytic, reversible anti-fertility, and an anti-proteolyticeffect, and said at least one drug comprising at least a guanidine, andsaid first walls of said intrauterine device comprising a polymer havinga predetermined permeability to said drug, whereby said predeterminedpermeability of said first walls controls the release rate of said drugfrom said cavity.
 31. The arrangement defined in claim 30 wherein:saidat least one drug is selected from the class consisting of:(a) a mixtureof an amidine and a guanidine; (b) a mixture of more than one amidineand a guanidine; (c) a mixture of an amidine and more than oneguanidine; (d) a mixture of more than one amidine and more than oneguanidine; (e) a guanidine; and (f) a mixture of more than oneguanidine.
 32. The arrangement defined in claim 30 wherein:saidguanidine of said at least one drug is selected from the classconsisting of:(a) aromatic monoguanidines; (b) aromatic diguanidines;(c) non-aromatic monoguanidines; and (d) non-aromatic diguanidines. 33.The arrangement defined in claim 30 wherein:said at least one drug isselected from the class of aromatic monoguanidines of the group:##STR43## wherein R is selected from the class consisting of: (a) acarbon chain free of other elements;(b) a carbon chain with at least oneother element; (c) an aromatic group free of additional carbon atoms,carbon chains and other elements; (d) an aromatic group with at leastone addition selected from the class consisting of carbon atoms, carbonchains and other elements; (e) a cyclic non-aromatic group free ofadditional carbon atoms, carbon chains and other elements; (f) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains, and other elements; and (g) acombination of at least two of (a), (b), (c), (d), (e) and (f); andwherein: ##STR44## represents the benzene ring.
 34. The arrangementdefined in claim 30 wherein:said at least one drug is selected from theclass of aromatic diguanidines of the group: ##STR45## and wherein eachguanidine group ##STR46## is in one of a meta or para position withrespect to R₁, and in which: R₁ is selected from the class consistingof:(a) a hydrocarbon chain free of ether and ester bonds to the benzenering; and (b) a hydrocarbon chain having at least one bond selected fromthe class of ether bonds and ester bonds to the benzene ring; R₂ and R₃are selected from the class consisting of:hydrogen, chlorine, bromine,iodine, hydroxyl group and alkyl group; and ##STR47## represents thebenzene ring.
 35. The arrangement defined in claim 30 wherein:said atleast one drug is selected from the class of non-aromatic monoguanidinesof the group: ##STR48## wherein R is selected from the class consistingof: (a) a carbon chain free of other elements;(b) a carbon chain with atleast one other element; (c) a cyclic non-aromatic group free ofadditional carbon atoms, carbon chains and other elements; (d) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains and other elements; (e) acombination of at least two of (a), (b), (c), and (d).
 36. Thearrangement defined in claim 30 wherein:said at least one drug isselected from the class consisting of non-aromatic diguanidines of thegroup: ##STR49## wherein R is selected from the class consisting of: (a)a carbon chain free of other elements;(b) a carbon chain with at leastone other element; (c) a cyclic non-aromatic group free of additionalcarbon atoms, carbon chains and other elements; (d) a cyclicnon-aromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains and other elements; (e) acombination of at least two of (a), (b), (c), and (d).
 37. Thearrangement defined in claim 30 wherein said at least one drug isselected from the class consisting of: ##STR50##
 38. The arrangementdefined in claim 30 and further comprising:a coating on at least a firstportion of said surface of said intrauterine device, and said coatingcomprising one of a:biodegradable cross-linked polymer, a biodegradablecross-linked co-polymer, a non-biodegradable monomer, anon-biodegradable dimer, a non-biodegradable oligomer, and anon-biodegradable cross-linked polymer of a second drug, and said seconddrug comprises at least a guanidine.
 39. The arrangement defined inclaim 38 wherein:said second drug is selected from the class consistingof:(a) a mixture of an amidine and a guanidine; (b) a mixture of morethan one amidine and a guanidine; (c) a mixture of an amidine and morethan one guanidine; (d) a mixture of more than one amidine and more thanone guanidine; (e) a guanidine; and (f) a mixture of more than oneguanidine.
 40. The arrangement defined in claim 38 wherein:saidguanidine of said at least one drug is selected from the classconsisting of:(a) aromatic monoguanidines; (b) aromatic diguanidines;(c) non-aromatic monoguanidines; and (d) non-aromatic diguanidines. 41.The arrangement defined in claim 38 wherein:said at least a guanidine ofsaid second drug is selected from the class consisting of aromaticmonoguanidines of the group: ##STR51## wherein R is selected from theclass consisting of: (a) a carbon chain free of other elements;(b) acarbon chain with at least one other element; (c) an aromatic group freeof additional carbon atoms, carbon chains and other elements; (d) anaromatic group with at least one addition selected from the classconsisting of carbon atoms, carbon chains and other elements; (e) acyclic non-aromatic group free of additional carbon atoms, carbon chainsand other elements; (f) a cyclic non-aromatic group with at least oneaddition selected from the class consisting of carbon atoms, carbonchains, and other elements; and (g) a combination of at least two of(a), (b), (c), (d), (e) and (f); and wherein: ##STR52## represents thebenzene ring.
 42. The arrangement defined in claim 38 wherein:said atleast a guanidine of said second drug is selected from the classconsisting of aromatic diguanidines of the group: ##STR53## and whereineach guanidine group ##STR54## is in one of a meta or para position withrespect to R₁, and in which: R₁ is selected from the class consistingof:(a) a hydrocarbon chain free of ether and ester bonds to the benzenering; and (b) a hydrocarbon chain free of ether and ester bonds selectedfrom the class of ether bonds and ester bonds to the benzene ring; R₂and R₃ are selected from the class consisting of: hydrogen, chlorine,bromine, iodine, hydroxyl group and alkyl group; and ##STR55##represents the benzene ring.
 43. The arrangement defined in claim 38wherein:said at least a guanidine of said second drug is selected fromthe class consisting of non-aromatic monoguanidines of the group:##STR56## wherein R is selected from the class consisting of: (a) acarbon chain free of other elements;(b) a carbon chain with at least oneother element; (c) a cyclic non-aromatic group free of additional carbonatoms, carbon chains and other elements; (d) a cyclic non-aromatic groupwith at least one addition selected from the class consisting of carbonatoms, carbon chains and other elements; (e) a combination of at leasttwo of (a), (b), (c), and (d).
 44. The arrangement defined in claim 38wherein:said at least a guanidine of said second drug is selected fromthe class consisting of the group: ##STR57## wherein R is selected fromthe class consisting of: (a) a carbon chain free of other elements;(b) acarbon chain with at least one other element; (c) a cyclic non-aromaticgroup free of additional carbon atoms, carbon chains and other elements;(d) a cyclic non-aromatic group with at least one addition selected fromthe class consisting of carbon atoms, carbon chains and other elements;(e) a combination of at least two of (a), (b), (c), and (d).
 45. Thearrangement defined in claim 38 wherein:said at least a guanidine ofsaid second drug is selected from the class consisting of the group:##STR58##
 46. The arrangement defined in claim 38 further comprising:acoating of copper on a second portion of said surface.